BACKGROUND: Congenital central hypoventilation syndrome (CCHS) is characterized by alveolar hypoventilation and autonomic dysregulation. PURPOSE: (1) To demonstrate the importance of PHOX2B testing in diagnosing and treating patients with CCHS, (2) to summarize recent advances in understanding how mutations in the PHOX2B gene lead to the CCHS phenotype, and (3) to provide an update on recommendations for diagnosis and treatment of patients with CCHS. METHODS: Committee members were invited on the basis of their expertise in CCHS and asked to review the current state of the science by independently completing literature searches. Consensus on recommendations was reached by agreement among members of the Committee. RESULTS: A review of pertinent literature allowed for the development of a document that summarizes recent advances in understanding CCHS and expert interpretation of the evidence for management of affected patients. CONCLUSIONS: A PHOX2B mutation is required to confirm the diagnosis of CCHS. Knowledge of the specific PHOX2B mutation aids in anticipating the CCHS phenotype severity. Parents of patients with CCHS should be tested for PHOX2B mutations. Maintaining a high index of suspicion in cases of unexplained alveolar hypoventilation will likely identify a higher incidence of milder cases of CCHS. Recommended management options aimed toward maximizing safety and optimizing neurocognitive outcome include: (1) biannual then annual in-hospital comprehensive evaluation with (i) physiologic studies during awake and asleep states to assess ventilatory needs during varying levels of activity and concentration, in all stages of sleep, with spontaneous breathing, and with artificial ventilation, and to assess ventilatory responsiveness to physiologic challenges while awake and asleep, (ii) 72-hour Holter monitoring, (iii) echocardiogram, (iv) evaluation of ANS dysregulation across all organ systems affected by the ANS, and (v) formal neurocognitive assessment; (2) barium enema or manometry and/or full thickness rectal biopsy for patients with a history of constipation; and (3) imaging for neural crest tumors in individuals at greatest risk based on PHOX2B mutation.